Allergy is a major health problem in countries with a Western lifestyle. Furthermore, the prevalence of allergic disease is increasing in these countries. Although allergy in general may not be considered a life-threatening disease, asthma annually causes a significant number of deaths. An exceptional prevalence in about 30% of teenagers conveys a substantial loss in quality of life, working days and money, and warrants a classification among major health problems in the Western world.
Clinical allergy manifestation and symptoms manifest themselves in several ways and may vary depending on the sensitized individual and the allergy inflicted. Common symptoms are edema, itching, redness and running of the eyes and nose (rhinitis and conjunctivitis) and symptoms of the upper and lower airway such as wheezing, coughing, shortness of breath, skin conditions like eczema, urticaria and itching. Other symptoms like fatigue or insomnia are also experienced. Symptomatic treatment aims at reducing or affecting severity of the symptoms or reducing the need for other drugs given in parallel. Symptomatic drugs include antihistamines like H1 and H2 receptor antagonists, intranasal and systemic corticosteroids, non-steroid anti-inflammatory drugs, nasal decongestants like adrenoceptor agonists. Treatment and relief of one or more allergic symptoms and/or the reduction in the need for other medication is a further object of this invention.
Allergen specific immunotherapy (also referred to as allergen immunotherapy, allergy immunotherapy, specific allergy vaccination (SAV), hyposensitization or desensitization) is a causal treatment of allergic disease. It interferes with basic immunological mechanisms resulting in persistent or long term improvement of the patients' immune status. Thus, the protective effect of specific allergy vaccination extends beyond the treatment period in contrast to symptomatic drug treatment. Some patients receiving the treatment are cured, and in addition, most patients experience a relief in disease severity and symptoms experienced, or at least an arrest in disease aggravation. Allergen immunotherapy also has preventive effects reducing the risk of hay fever developing into asthma, and reducing the risk of developing new sensitivities.
Conventional allergen immunotherapy is carried out using multiple administration of allergen applied over an extended time period.
A long standing use of allergen immunotherapy is via the injection route (also called SCIT, SIT or subcutaneous immunotherapy). Commonly, allergen is administered via the subcutaneous route in incremental doses until a maintenance dose is reached, but also treatment regimens with cluster administration or without up-dosing are used. Allergen may be administered for a period up till 3 years or more before treatment is completed or ceased depending on the treatment schedule applied.
An alternative administration route is sublingual (SLIT) administration which is more convenient for the patients as administration may be carried out at home.
The immunotherapy products for use in immunotherapy typically comprise the allergen that causes the allergy in the patient or derivatives thereof as the active ingredient, which may be formulated in various ways according to the administration route of choice such as aqueous formulations, aluminum hydroxide suspensions or allergoids. The active ingredient may for example be an aqueous extract of pollen containing pollen allergens and/or aqueous extract of mites containing mite allergens.
The most important house dust mites belonging to the family of Pyroglyphidae include Euroglyphus maynei, Dermatophagoides pteronyssinus and Dermatophagoides farinae. These are found in most of the world including Europe, USA, China and many other counties and allergy and allergic asthma caused by house dust mites is a common disease afflicting 25% of the population.
Some patients are sensitized to Euroglyphus maynei, Dermatophagoides pteronyssinus, some others to Dermatophagoides farinae and others to both species.
Patients are normally sensitized (although to a variable degree) to the two major allergens in house dust mites, namely group 1 allergen and/or group 2 allergen.
House dust mites contain more than 20 different allergens. However, the two major allergens group 1 and group 2 are the most important allergens because of the frequency of patients sensitized to these two allergens, the amount of IgE produced in response to these allergens and the content thereof in natural extracts.
In allergen immunotherapy patients are treated with allergens that they are sensitized to. The ability of allergens to elicit IgE mediated immunologically responses makes it important to control the allergen content especially group 1 and group 2 allergens in the allergen extracts administered to allergic patients to avoid side effects.
The group 1 and 2 allergens from Der f and Der p are closely related but not identical, see Allergens and Allergen Immunotherapy, Clinical Allergy and Immunology Series 21, Lockey and Ledfors, 4th ed., page 162-164).
All the products on the market today for immunotherapy of patients with house dust mite allergy comprises aqueous allergen extracts containing group 1 and group 2 mite allergen. Many products contain extracts of both Dermatophagoides pteronyssinus and Dermatophagoides farinae. 
Mite allergen extracts are usually prepared by cultivation of mites in a suitable mite medium followed by extraction of the whole mite culture or extraction of a mite body fraction thereof, Allergens and Allergy Immunotherapy, Fourth Edition, Clinical Allergy and Immunotherapy, series 21, Ed: R. F. Lockey and D. K. Ledfors, page 286.
In the manufacture of allergen extract it is important to control the variability and to achieve consistency and reproducibility for optimal safety and efficacy in a subsequent clinical setting. Standardization of allergen extract are is a complex matter and in principle involves the entire production chain of processes including establishment of robust and reproducible manufacturing procedures, see Allergy Methods and Protocols, Jones and Lympany (2008), chapter 12 and 13. Because of the IgE binding capacity of an allergen extract is related to the content of one or a few major allergens the general standardization strategy normally involves standardizing the extract in respect to content of a selection of these major allergens further to overall IgE binding potency and composition. Relevant method for assays to access allergen extracts are well known in the art and include immunoelectrophoresis assay such as CIE, CRIE, FRIE, CLIE, quantification methods using mono- or polyspecific antibodies such as SRID, RIS, QIE as well as methods of making standardization references. International standards exist to a limited extent, one example being the FDA; CBER reference provided for extract manufactures to standardize against and label their product with resulting in a biopotency label of AI or BAU (Allergy Units or Bioequivalent Allergy Units).
There is considerable batch to batch variation in the amount by weight of group 1 and group 2 allergens in allergen extracts and the amount by weight of group 1 allergen in these allergen extracts is typically higher than the amount of group 2 allergen by weight.
It is well known that the house dust mite group 1 and group 2 allergens are found in both the bodies of the mite and in the faecal particles produced by the mites during cultivation. It is also known that group 1 allergen is associated with the faecal particles and the group 2 allergen is associated with the mite bodies; see Batard et al. Int Arch Allergy Immunol 2006, 140, p. 295-305.
As mentioned above there is a considerable batch to batch variation in the content of mite group 1 and mite group 2 allergens in batches of whole mite culture extracts, including extracts of mite bodies, which makes it very difficult to prepare mite extracts with a constant and predetermined level of group 1 and group 2 allergen. This is of course a serious problem in the industrial or large scale production of a pharmaceutical product which should contain as closely as possible the same amount of active ingredient(s) in every batch.
Therefore improved processes and product(s) are important to maximize production efficiency as well as provide high quality products for end-user efficacy and safety.